A Medical Research Study Designed to Determine if Venglustat Can be a Future Treatment for ADPKD Patients (STAGED-PKD)

• ClinicalTrials.gov Identifier: NCT03523728
• Recruitment Status: Terminated
• First Posted: May 14, 2018
• Results First Posted: November 9, 2022
• Last Update Posted: November 9, 2022
• Sponsor: Genzyme, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Genzyme, a Sanofi Company )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Polycystic Kidney, Autosomal Dominant
• Interventions: Drug: Venglustat; Drug: Placebo
• Enrollment: 478

Participant Flow

Recruitment Details	This study was conducted at 93 sites that enrolled participants in 23 countries. A total of 478 participants were enrolled from 04 October 2018 to 01 June 2021. Study was conducted in 2 stages: Stage 1 and Stage 2.
Pre-assignment Details	Participants who completed 24 months of treatment in either Stage 1 or Stage 2 of EFC15392 had option to enroll in an open-label long-term extension study LTS15823 (NCT ID: NCT04705051).

Arm/Group Title	Stage 1- Placebo	Stage 1- Venglustat 8 mg	Stage 1- Venglustat 15 mg	Stage 2- Placebo	Stage 2- Venglustat 15 mg
Arm/Group Description	Participants from Stage 1 were randomized to receive 2 capsules of placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 milligrams (mg) (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive 1 capsule of venglustat 15 mg and 1 capsule of placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 2 were randomized to receive 1 capsule of placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.
Period Title: Stage 1 (24 Months)
Started	78	78	80	0	0
Completed	12	10	12	0	0
Not Completed	66	68	68	0	0
Reason Not Completed
Adverse Event	2	2	4	0	0
Progressive disease	0	0	1	0	0
Lack of Efficacy	2	0	0	0	0
Poor compliance to protocol	1	0	0	0	0
Withdrawal by Subject	6	5	7	0	0
Study terminated by sponsor	54	59	56	0	0
Other-Unspecified	1	2	0	0	0
Period Title: Stage 2 (24 Months)
Started	0	0	0	123 [1]	119 [1]
Treated	0	0	0	122	119
Estimated Glomerular Filtration Rate (eGFR) Between 45 and 89.9 mL/Min/1.73 m^2 at Screening	0	0	0	97	90
eGFR Between 30 and 44.9 mL/Min/1.73 m^2 at Screening	0	0	0	25	29
Completed	0	0	0	0	0
Not Completed	0	0	0	123	119
Reason Not Completed
Adverse Event	0	0	0	1	2
Withdrawal by Subject	0	0	0	0	4
Study terminated by sponsor	0	0	0	119	110
Other-Unspecified	0	0	0	2	3
Randomized and not treated	0	0	0	1	0
[1] Stage 1 and Stage 2 were separate population.

Baseline Characteristics

Arm/Group Title		Stage 1- Placebo	Stage 1- Venglustat 8 mg	Stage 1- Venglustat 15 mg	Stage 2- Placebo	Stage 2- Venglustat 15 mg	Total Title
Arm/Group Description		Participants from Stage 1 were randomized to receive 2 capsules of placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive 1 capsule of venglustat 15 mg and 1 capsule of placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 2 were randomized to receive 1 capsule of placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.	[Not Specified]
Overall Number of Baseline Participants		78	78	80	123	119	478
Baseline Analysis Population Description		Analysis was performed on all participants randomized in the study.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	78 participants	78 participants	80 participants	123 participants	119 participants	478 participants
		42.6 (6.0)	41.7 (6.9)	43.6 (5.7)	41.7 (6.9)	42.1 (6.7)	42.2 (6.5)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	78 participants	78 participants	80 participants	123 participants	119 participants	478 participants
	Female	37 47.4%	31 39.7%	34 42.5%	46 37.4%	48 40.3%	196 41.0%
	Male	41 52.6%	47 60.3%	46 57.5%	77 62.6%	71 59.7%	282 59.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	78 participants	78 participants	80 participants	123 participants	119 participants	478 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	1 0.8%	0 0.0%	1 0.2%
	Asian	27 34.6%	27 34.6%	27 33.8%	52 42.3%	55 46.2%	188 39.3%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	1 1.3%	0 0.0%	0 0.0%	1 0.2%
	Black or African American	0 0.0%	1 1.3%	0 0.0%	2 1.6%	0 0.0%	3 0.6%
	White	48 61.5%	50 64.1%	52 65.0%	66 53.7%	64 53.8%	280 58.6%
	More than one race	1 1.3%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	1 0.2%
	Unknown or Not Reported	2 2.6%	0 0.0%	0 0.0%	2 1.6%	0 0.0%	4 0.8%

Outcome Measures

1. Primary Outcome

Title	Annualized Slope of Change in Total Kidney Volume (TKV) From Baseline to Month 18: Stage 1
Description	Total kidney volume is a measure for assessing disease progression in participants with ADPKD, a prognostic biomarker of renal function decline and progression to end-stage renal disease. Kidney volume was assessed using magnetic resonance imaging (MRI). The annualized slope of change in TKV (in percentage [%] per year) in each treatment group was obtained from the back-transformation of the mean slope of log10-transformed TKV obtained from the linear mixed effect model. The model included fix effects of treatment (venglustat 15 mg, venglustat 8 mg or placebo), mayo imaging classification (as per randomization stratification factor: class 1C versus 1D versus 1E), time (as continuous variable in years), treatment * time interaction and mayo imaging classification * time interaction and included random intercept and slope.
Time Frame	From Baseline to Month 18

Outcome Measure Data

Analysis Population Description

Analysis was performed on Stage 1 intent-to-treat (ITT) population that includes all participants randomized in Stage 1 and were analyzed according to the intervention allocated by randomization (venglustat 15 mg, venglustat 8 mg or placebo). Here, 'Overall number of participants analyzed' signifies participants who were evaluable for the outcome measure.

Arm/Group Title	Stage 1- Placebo	Stage 1- Venglustat 8 mg	Stage 1- Venglustat 15 mg
Arm/Group Description:	Participants from Stage 1 were randomized to receive 2 capsules of placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive 1 capsule of venglustat 15 mg and 1 capsule of placebo matched to venglustat once daily for treatment period of 24 months.
Overall Number of Participants Analyzed	78	78	79
Geometric Least Squares Mean (95% Confidence Interval); Unit of Measure: percent change in TKV/year
	6.35; (5.10 to 7.62)	7.71; (6.46 to 8.98)	6.38; (5.11 to 7.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1- Placebo, Stage 1- Venglustat 8 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.1367
	Comments	[Not Specified]
	Method	linear mixed effect model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Relative difference
	Estimated Value	21.32
	Confidence Interval	(2-Sided) 95%; -5.77 to 58.22
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage 1- Placebo, Stage 1- Venglustat 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.9812
	Comments	[Not Specified]
	Method	linear mixed effect model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Relative difference
	Estimated Value	0.34
	Confidence Interval	(2-Sided) 95%; -24.57 to 33.36
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Annualized Rate of Change in Estimated Glomerular Filtration Rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) From Baseline to Month 24: Combined Stage 1 and Stage 2
Description	An eGFR was used to measure level of kidney function and determine the stage of kidney disease in ADPKD participants. Baseline eGFR was defined for each participant as the average of eGFR values assessed prior or equal to first dose of study drug or randomization for participants randomized and not exposed. Annualized rate of change in eGFR in each treatment group was obtained from the linear mixed effect model including the fixed categorical effects of treatment group (venglustat 15 mg, venglustat 8 mg or placebo), mayo imaging classification (as per interactive response technology [IRT]: 1C, 1D, 1E), time (as continuous variable in years), treatment-by-time, mayo imaging classification-by-time, and included random intercept and slope.
Time Frame	From Baseline to Month 24

Outcome Measure Data

Analysis Population Description

Analysis was performed on Combined Stage 1 and Stage 2 ITT population that included all participants with an eGFR between 45 and 89.9 mL/min/1.73 m^2 at screening who are randomized in Stage 1 or Stage 2 and were analyzed according to the intervention allocated by randomization (venglustat 15 mg, venglustat 8 mg or placebo). Data for this outcome measure (OM) was planned to be collected and analyzed for combined Stage 1 and Stage 2 population as pre-specified in protocol.

Arm/Group Title	Placebo	Venglustat 8 mg	Venglustat 15 mg
Arm/Group Description:	All participants from Stage 1 or Stage 2 were randomized to receive placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	All participants from Stage 1 or Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.
Overall Number of Participants Analyzed	175	78	170
Least Squares Mean (95% Confidence Interval); Unit of Measure: mL/min/1.73 m^2/year
	-2.40; (-3.30 to -1.49)	-4.82; (-5.82 to -3.83)	-4.89; (-5.80 to -3.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Venglustat 8 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.0005
	Comments	[Not Specified]
	Method	linear mixed effect model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Relative difference
	Estimated Value	101.32
	Confidence Interval	(2-Sided) 95%; 35.63 to 233.72
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Venglustat 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.0002
	Comments	[Not Specified]
	Method	linear mixed effect model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Relative difference
	Estimated Value	104.17
	Confidence Interval	(2-Sided) 95%; 39.54 to 236.45
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Annualized Rate of Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Month 24: Stage 1
Description	An eGFR was used to measure level of kidney function and determine the stage of kidney disease in ADPKD participants. Baseline eGFR was defined for each participant as the average of eGFR values assessed prior or equal to first dose of study drug or randomization for participants randomized and not exposed. Annualized rate of change in eGFR was obtained from the linear mixed effect model including the fixed categorical effects of treatment group, mayo imaging classification (as per IRT), time (as continuous variable in years), treatment-by-time, mayo imaging classification-by-time, and included random intercept and slope. Due to early termination of study for futility, the two-steps analysis initially planned was not applicable, then the annualized rate of change from baseline in eGFR in Stage 1 population were assessed using all data available up to database lock (i.e., including Month 24 assessment). As this is a slope, it allowed to have more data and to reduce variability.
Time Frame	From Baseline to Month 24

Outcome Measure Data

Analysis Population Description

Analysis was performed on Stage 1 ITT population.

Arm/Group Title	Stage 1- Placebo	Stage 1- Venglustat 8 mg	Stage 1- Venglustat 15 mg
Arm/Group Description:	Participants from Stage 1 were randomized to receive 2 capsules of placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive 1 capsule of venglustat 15 mg and 1 capsule of placebo matched to venglustat once daily for treatment period of 24 months.
Overall Number of Participants Analyzed	78	78	80
Least Squares Mean (95% Confidence Interval); Unit of Measure: mL/min/1.73 m^2/year
	-3.14; (-4.09 to -2.18)	-4.74; (-5.68 to -3.80)	-4.59; (-5.53 to -3.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1- Placebo, Stage 1- Venglustat 8 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.0197
	Comments	[Not Specified]
	Method	linear mixed effect model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Relative difference
	Estimated Value	51.01
	Confidence Interval	(2-Sided) 95%; 7.01 to 125.45
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage 1- Placebo, Stage 1- Venglustat 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.0337
	Comments	[Not Specified]
	Method	linear mixed effect model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Relative difference
	Estimated Value	46.36
	Confidence Interval	(2-Sided) 95%; 3.21 to 119.01
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Annualized Slope of Change in Total Kidney Volume (TKV) From Baseline to Month 18: Combined Stage 1 and Stage 2
Description	Total kidney volume is a measure for assessing disease progression in participants with ADPKD, a prognostic biomarker of renal function decline and progression to end-stage renal disease. Kidney volume was assessed using MRI. The annualized slope of change in TKV (in % per year) in each treatment group was obtained from the back-transformation of the mean slope of log10-transformed TKV obtained from the linear mixed effect model. The model included fix effects of treatment (venglustat 15 mg, venglustat 8 mg or placebo), mayo imaging classification (as per randomization stratification factor: class 1C versus 1D versus 1E), time (as continuous variable in years), treatment * time interaction and mayo imaging classification * time interaction and included random intercept and slope.
Time Frame	From Baseline to Month 18

Outcome Measure Data

Analysis Population Description

As no post-baseline MRI data were collected in Stage 2 due to early study discontinuation, the analysis of TKV in Combined Stage 1 and Stage 2 was not done.

Arm/Group Title	Placebo	Venglustat 8 mg	Venglustat 15 mg
Arm/Group Description:	All participants from Stage 1 or Stage 2 were randomized to receive placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	All participants from Stage 1 or Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.
Overall Number of Participants Analyzed	0	0	0

No data displayed because Outcome Measure has zero total analyzed.

5. Secondary Outcome

Title	Change in Pain Severity as Measured by Brief Pain Inventory-Short Form (BPI-SF)-Item 3 Scale Score From Baseline to Month 18: Stage 1
Description	The BPI-SF is a validated, self-administered questionnaire designed to measure a participant's perceived level of pain. The BPI-SF consisted of 15 items that use a numeric rating scale (NRS) to assess pain severity and pain interference in the past 24 hours and the past week. BPI-SF Item 3 asks participants to "Please rate your pain by marking the box beside the number that best describes your pain at its worst in the past 24 hours." The NRS ranged from 0 (no pain) to 10 (worst imaginable pain), where higher scores indicates greater intensity of pain. Least-squares (LS) means, and standard errors (SE) were estimated from mixed-effect model with repeated measures (MMRM) analysis.
Time Frame	From Baseline to Month 18

Outcome Measure Data

Analysis Population Description

Analysis was performed on Stage 1 ITT population. Here, 'Overall number of participants analyzed' signifies participants who were evaluable for the outcome measure.

Arm/Group Title	Stage 1- Placebo	Stage 1- Venglustat 8 mg	Stage 1- Venglustat 15 mg
Arm/Group Description:	Participants from Stage 1 were randomized to receive 2 capsules of placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive 1 capsule of venglustat 15 mg and 1 capsule of placebo matched to venglustat once daily for treatment period of 24 months.
Overall Number of Participants Analyzed	69	65	65
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-0.09 (0.15)	0.01 (0.17)	-0.35 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1- Placebo, Stage 1- Venglustat 8 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.6374
	Comments	[Not Specified]
	Method	Mixed effect model with repeated measure
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; -0.342 to 0.556
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.23
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage 1- Placebo, Stage 1- Venglustat 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.2560
	Comments	[Not Specified]
	Method	Mixed effect model with repeated measure
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.689 to 0.185
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.22
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Change in Pain Severity as Measured by Brief Pain Inventory-Short Form (BPI-SF)-Item 3 Scale Score From Baseline to Month 24: Combined Stage 1 and Stage 2
Description	The BPI-SF is a validated, self-administered questionnaire designed to measure a participant's perceived level of pain. The BPI-SF consisted of 15 items that use a NRS to assess pain severity and pain interference in the past 24 hours and the past week. BPI-SF Item 3 asks participants to "Please rate your pain by marking the box beside the number that best describes your pain at its worst in the past 24 hours." The NRS ranged from 0 (no pain) to 10 (worst imaginable pain), where higher scores indicate greater intensity of pain. LS means and SE were estimated from MMRM analysis.
Time Frame	From Baseline to Month 24

Outcome Measure Data

Analysis Population Description

Analysis was performed on Combined Stage 1 and Stage 2 ITT population. Here, 'Overall number of participants analyzed' signifies participants who were evaluable for the outcome measure. Data for this OM was planned to be collected and analyzed for combined Stage 1 and Stage 2 population as pre-specified in protocol.

Arm/Group Title	Placebo	Venglustat 8 mg	Venglustat 15 mg
Arm/Group Description:	All participants from Stage 1 or Stage 2 were randomized to receive placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	All participants from Stage 1 or Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.
Overall Number of Participants Analyzed	133	65	126
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-0.20 (0.23)	-0.31 (0.36)	-0.36 (0.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Venglustat 8 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.7900
	Comments	[Not Specified]
	Method	Mixed effect model with repeated measure
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -0.971 to 0.747
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.42
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Venglustat 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.6322
	Comments	[Not Specified]
	Method	Mixed effect model with repeated measure
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.808 to 0.500
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.32
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Change in Fatigue Severity as Measured by Brief Fatigue Inventory (BFI-SF)-Item 3 Scale Score From Baseline to Month 18: Stage 1
Description	The BFI-SF is a 10-item, validated, self-administered questionnaire that was originally developed to assess fatigue severity. The 10-items were measured on a 0-10 scale, with 0 being 'does not interfere' and 10 being 'completely interferes.' BFI - Item 3 asks participants to 'Please rate your fatigue (weariness, tiredness) by circling the one number that best describes your worst level of fatigue during the past 24 hours. The NRS ranged from 0 (no fatigue) to 10 (worst imaginable fatigue). Higher global scores were associated with more severe fatigue. LS means and SE were estimated from MMRM analysis.
Time Frame	From Baseline to Month 18

Outcome Measure Data

Analysis Population Description

Analysis was performed on Stage 1 ITT population. Here, 'Overall number of participants analyzed' signifies participants who were evaluable for the outcome measure.

Arm/Group Title	Stage 1- Placebo	Stage 1- Venglustat 8 mg	Stage I- Venglustat 15 mg
Arm/Group Description:	Participants from Stage 1 were randomized to receive 2 capsules of placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive 1 capsule of venglustat 15 mg and 1 capsule of placebo matched to venglustat once daily for treatment period of 24 months.
Overall Number of Participants Analyzed	69	65	65
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-0.26 (0.23)	-0.10 (0.25)	-0.64 (0.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage 1- Placebo, Stage 1- Venglustat 8 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.6245
	Comments	[Not Specified]
	Method	Mixed effect model with repeated measure
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	0.17
	Confidence Interval	(2-Sided) 95%; -0.506 to 0.839
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.34
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage 1- Placebo, Stage I- Venglustat 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.2567
	Comments	[Not Specified]
	Method	Mixed effect model with repeated measure
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95%; -1.044 to 0.281
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.33
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	Change in Fatigue Severity as Measured by Brief Fatigue Inventory (BFI-SF)-Item 3 Scale Score From Baseline to Month 24: Combined Stage 1 and Stage 2
Description	The BFI-SF is a 10-item, validated, self-administered questionnaire that was originally developed to assess fatigue severity. The 10-items were measured on a 0-10 scale, with 0 being 'does not interfere' and 10 being 'completely interferes.' BFI - Item 3 asks participants to "Please rate your fatigue (weariness, tiredness) by circling the one number that best describes your worst level of fatigue during the past 24 hours. The NRS ranged from 0 (no fatigue) to 10 (worst imaginable fatigue). Higher global scores were associated with more severe fatigue. LS means and SE were estimated from MMRM analysis.
Time Frame	From Baseline to Month 24

Outcome Measure Data

Analysis Population Description

Analysis was performed on Combined Stage 1 and Stage 2 ITT population. Here, 'Overall number of participants analyzed' signifies participants who were evaluable for the outcome measure. Data for this OM was planned to be collected and analyzed for combined Stage 1 and Stage 2 population as pre-specified in protocol.

Arm/Group Title	Placebo	Venglustat 8 mg	Venglustat 15 mg
Arm/Group Description:	All participants from Stage 1 or Stage 2 were randomized to receive placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	All participants from Stage 1 or Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.
Overall Number of Participants Analyzed	133	65	126
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	0.02 (0.38)	-0.85 (0.55)	-0.51 (0.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Venglustat 8 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.2023
	Comments	[Not Specified]
	Method	Mixed effect model with repeated measure
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	-0.87
	Confidence Interval	(2-Sided) 95%; -2.232 to 0.485
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.68
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Venglustat 15 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.3205
	Comments	[Not Specified]
	Method	Mixed effect model with repeated measure
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	-0.54
	Confidence Interval	(2-Sided) 95%; -1.610 to 0.537
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.53
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Pharmacokinetics: Plasma Concentration of Venglustat: Stage 1
Description	Venglustat plasma concentrations was determined using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Data for this outcome measure was not planned to be collected and analyzed for placebo arm.
Time Frame	Day 1: 3 hours Post-Dose, Month 1: Pre-Dose and 3 hours Post-Dose, Month 6: Pre-Dose, Month 18: Pre-Dose

Outcome Measure Data

Analysis Population Description

Analysed on Stage 1 pharmacokinetic (PK) population that included all participants randomized in Stage 1 who took at least one dose of study drug and had at least one post-baseline PK assessment; analyzed according to the intervention they actually received. Here, "number analyzed" signifies participants with available data for each specified category.

Arm/Group Title		Stage 1- Venglustat 8 mg	Stage 1- Venglustat 15 mg
Arm/Group Description:		Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive 1 capsule of venglustat 15 mg and 1 capsule of placebo matched to venglustat once daily for treatment period of 24 months.
Overall Number of Participants Analyzed		78	80
Mean (Standard Deviation); Unit of Measure: nanograms per milliliter
Day 1: 3 hours Post-Dose	Number Analyzed	65 participants	73 participants
		27.8 (11.9)	50.9 (22.5)
Month 1: Pre-Dose	Number Analyzed	72 participants	63 participants
		54.7 (19.2)	103.9 (50.2)
Month 1: 3 hours Post-Dose	Number Analyzed	75 participants	64 participants
		82.1 (24.7)	154.6 (61.1)
Months 6: Pre-Dose	Number Analyzed	47 participants	54 participants
		57.5 (23.5)	106.2 (56.3)
Months 18: Pre-Dose	Number Analyzed	41 participants	41 participants
		58.3 (22.0)	120.3 (73.1)

10. Secondary Outcome

Title	Pharmacokinetics: Plasma Concentration of Venglustat: Stage 2
Description	Venglustat plasma concentrations was determined using a validated LC-MS/MS method. Data for this outcome measure was not planned to be collected and analyzed for placebo arm.
Time Frame	Month 1: Pre-dose and 3 hours Post-dose

Outcome Measure Data

Analysis Population Description

Analysis was performed on Stage 2 PK population that included all participants with an eGFR between 45 and 89.9 mL/min/1.73 m^2 at screening who were randomized in Stage 2, who took at least one dose of study drug and who had at least one post-baseline PK assessment. Participants were analyzed according to study drug they actually received. Here, "number analyzed" signifies participants with available data for each specified category.

Arm/Group Title		Stage 2- Venglustat 15 mg
Arm/Group Description:		Participants from Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.
Overall Number of Participants Analyzed		77
Mean (Standard Deviation); Unit of Measure: nanograms per milliliter
Month 1: Pre-Dose	Number Analyzed	60 participants
		109.3 (60.7)
Month 1: 3 hours Post-Dose	Number Analyzed	61 participants
		163.5 (79.7)

11. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs): Stage 1
Description	An adverse event (AE) was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. A serious adverse event (SAE) was any untoward medical occurrence that at any dose: results in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was a medically important event. TEAEs were AEs that developed, worsened or became serious during the treatment-emergent (TE) period (defined as the time from the first investigational medicinal product [IMP] administration up to the last IMP administration in EFC15392 study + 30 days or up to the first visit in LTS15823 study, whichever comes earlier).
Time Frame	From the first IMP administration up to the last IMP administration in EFC15392 study + 30 days (i.e., up to 25 months) or up to the first visit in LTS15823 study, whichever comes earlier

Outcome Measure Data

Analysis Population Description

Analysis was performed on Stage 1 safety population that included all participants randomized in Stage 1 who took at least one dose or part of a dose of the double-blind IMP, analyzed according to the treatment actually received (venglustat 15 mg, venglustat 8 mg, or placebo)

Arm/Group Title	Stage 1- Placebo	Stage 1- Venglustat 8 mg	Stage 1- Venglustat 15 mg
Arm/Group Description:	Participants from Stage 1 were randomized to receive 2 capsules of placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive 1 capsule of venglustat 15 mg and 1 capsule of placebo matched to venglustat once daily for treatment period of 24 months.
Overall Number of Participants Analyzed	78	78	80
Measure Type: Count of Participants; Unit of Measure: Participants
TEAEs	62 79.5%	65 83.3%	70 87.5%
TESAEs	8 10.3%	15 19.2%	19 23.8%

12. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs): Combined Stage 1 and Stage 2
Description	An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. SAE was any untoward medical occurrence that at any dose: results in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was a medically important event. TEAEs were AEs that developed, worsened or became serious during the TE period (defined as the time from the first IMP administration up to the last IMP administration in EFC15392 study + 30 days or up to the first visit in LTS15823 study, whichever comes earlier).
Time Frame	From the first IMP administration up to the last IMP administration in EFC15392 study + 30 days (i.e., up to 25 months) or up to the first visit in LTS15823 study, whichever comes earlier

Outcome Measure Data

Analysis Population Description

Analysis was performed on extended Combined Stage 1 and Stage 2 safety population that included all participants with an eGFR between 45 and 89.9 mL/min/1.73 m^2 at screening who were randomized in Stage 1 or Stage 2 and who took at least one dose or part of a dose of IMP, analyzed according to treatment actually received. Data for this OM was planned to be collected and analyzed for combined Stage 1 and Stage 2 population as pre-specified in protocol.

Arm/Group Title	Placebo	Venglustat 8 mg	Venglustat 15 mg
Arm/Group Description:	All participants from Stage 1 or Stage 2 were randomized to receive placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	All participants from Stage 1 or Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.
Overall Number of Participants Analyzed	200	78	199
Measure Type: Count of Participants; Unit of Measure: Participants
TEAEs	128 64.0%	65 83.3%	143 71.9%
TESAEs	14 7.0%	15 19.2%	26 13.1%

13. Secondary Outcome

Title	Number of Participants With Potentially Clinically Significant Abnormalities: Hematology: Combined Stage 1 and Stage 2
Description	Criteria for potentially clinically significant abnormalities: Hemoglobin: less than or equal to (<=) 115 grams per liter (g/L) [Male]; <=95 g/L [Female]; greater than or equal to (>=) 185 g/L [Male]; >=165 g/L [Female]; Decrease from baseline >=20 g/L; Hematocrit: <=0.37 volume/volume (v/v) [Male]; <=0.32 v/v [Female]; >=0.55 v/v [Male]; >=0.5 v/v [Female]; Erythrocyte (red blood cells [RBC]): >=6*10^12 per liter (/L); Platelet: less than (<) 100*10^9/L; >=700*10^9/L; Leukocyte (white blood cells [WBC]): <3*10^9/L [Non-Black]; <2*10^9/L [Black], >=16*10^9/L; Neutrophils: <1.5*10^9/L [Non-Black]; <1*10^9/L [Black]; Lymphocytes: greater than (>) 4*10^9/L, Monocytes: >0.7*10^9/L; Basophils: >0.1*10^9/L; and Eosinophils: >0.5*10^9/L or >upper limit of normal (ULN) (if ULN >=0.5*10^9/L).
Time Frame	From the first IMP administration up to the last IMP administration in EFC15392 study + 30 days (i.e., up to 25 months) or up to the first visit in LTS15823 study, whichever comes earlier

Outcome Measure Data

Analysis Population Description

Analysis was performed on extended Combined Stage 1 and Stage 2 safety population. Here, "number analyzed" signifies participants with available data for specified category. Data for this OM was planned to be collected and analyzed for combined Stage 1 and Stage 2 population as pre-specified in protocol.

Arm/Group Title		Placebo	Venglustat 8 mg	Venglustat 15 mg
Arm/Group Description:		All participants from Stage 1 or Stage 2 were randomized to receive placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	All participants from Stage 1 or Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.
Overall Number of Participants Analyzed		200	78	199
Measure Type: Count of Participants; Unit of Measure: Participants
Hemoglobin: <=115 g/L (Male); <=95 g/L (Female)	Number Analyzed	187 participants	78 participants	190 participants
		7 3.7%	3 3.8%	5 2.6%
Hemoglobin: >=185 g/L (Male); >=165 g/L (Female)	Number Analyzed	187 participants	78 participants	190 participants
		0 0.0%	0 0.0%	0 0.0%
Hemoglobin: Decrease from baseline >=20 g/L	Number Analyzed	186 participants	78 participants	190 participants
		4 2.2%	7 9.0%	5 2.6%
Hematocrit: <=0.37 v/v (Male); <=0.32 v/v (Female)	Number Analyzed	186 participants	78 participants	190 participants
		40 21.5%	20 25.6%	42 22.1%
Hematocrit: >=0.55 v/v (Male); >=0.5 v/v (Female)	Number Analyzed	186 participants	78 participants	190 participants
		0 0.0%	0 0.0%	0 0.0%
Erythrocyte (RBC): >=6 * 10^12/L	Number Analyzed	187 participants	78 participants	190 participants
		1 0.5%	0 0.0%	1 0.5%
Platelet: <100*10^9/L	Number Analyzed	187 participants	78 participants	190 participants
		0 0.0%	2 2.6%	1 0.5%
Platelet: >=700*10^9/L	Number Analyzed	187 participants	78 participants	190 participants
		0 0.0%	0 0.0%	0 0.0%
Leukocyte (WBC): <3*10^9/L (Non-Black); <2*10^9/L (Black)	Number Analyzed	187 participants	78 participants	190 participants
		1 0.5%	2 2.6%	4 2.1%
Leukocyte (WBC): >=16*10^9/L	Number Analyzed	187 participants	78 participants	190 participants
		0 0.0%	2 2.6%	1 0.5%
Neutrophils: <1.5*10^9/L (Non-Black); <1*10^9/L (Black)	Number Analyzed	187 participants	78 participants	190 participants
		1 0.5%	1 1.3%	3 1.6%
Lymphocytes: >4*10^9/L	Number Analyzed	187 participants	78 participants	190 participants
		0 0.0%	1 1.3%	0 0.0%
Monocytes >0.7*10^9/L	Number Analyzed	187 participants	78 participants	190 participants
		6 3.2%	3 3.8%	7 3.7%
Basophils: >0.1*10^9/L	Number Analyzed	187 participants	78 participants	190 participants
		33 17.6%	5 6.4%	8 4.2%
Eosinophils: >0.5*10^9/L or >ULN	Number Analyzed	187 participants	78 participants	190 participants
		7 3.7%	2 2.6%	1 0.5%

14. Secondary Outcome

Title	Number of Participants With Potentially Clinically Significant Abnormalities: Clinical Chemistry: Combined Stage 1 and Stage 2
Description	Criteria for potentially clinically significant abnormalities: Glucose: <=3.9 millimoles per liter (mmol/L) and <lower limit of normal (LLN): >=11.1 mmol/L (unfasted); >=7 mmol/L (fasted); Albumin:<=25 g/L; Sodium: <=129 mmol/L; >=160 mmol/L; Potassium: <3 mmol/L; >=5.5 mmol/L; Chloride: <80 mmol/L, >115 mmol/L; Creatinine: >=150 micro millimoles per liter (mcmol/L) (Adults); >=30% change from Baseline; >=100% change from Baseline, Urea Nitrogen: >=17 mmol/L; Alanine Aminotransferase (ALT): >3 ULN; Aspartate Aminotransferase (AST): >3 ULN; Alkaline Phosphatase: >1.5 ULN; Total Bilirubin: >1.5 ULN, >2 ULN; ALT >3 ULN and Bilirubin >2 ULN; and Direct Bilirubin >35% Bilirubin and Bilirubin >1.5 ULN.
Time Frame	From the first IMP administration up to the last IMP administration in EFC15392 study + 30 days (i.e., up to 25 months) or up to the first visit in LTS15823 study, whichever comes earlier

Outcome Measure Data

Analysis Population Description

Analysis was performed on extended Combined Stage 1 and Stage 2 safety population. Here, "number analyzed" signifies participants with available data for each specified category. Data for this OM was planned to be collected and analyzed for combined Stage 1 and Stage 2 population as pre-specified in protocol.

Arm/Group Title		Placebo	Venglustat 8 mg	Venglustat 15 mg
Arm/Group Description:		All participants from Stage 1 or Stage 2 were randomized to receive placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	All participants from Stage 1 or Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.
Overall Number of Participants Analyzed		200	78	199
Measure Type: Count of Participants; Unit of Measure: Participants
Glucose: <=3.9 mmol/L and <LLN	Number Analyzed	196 participants	78 participants	196 participants
		17 8.7%	5 6.4%	12 6.1%
Glucose: >=11.1 mmol/L (unfasted); >=7 mmol/L (fasted)	Number Analyzed	196 participants	78 participants	196 participants
		10 5.1%	5 6.4%	19 9.7%
Albumin: <=25 g/L	Number Analyzed	196 participants	78 participants	196 participants
		0 0.0%	0 0.0%	0 0.0%
Sodium: <=129 mmol/L	Number Analyzed	196 participants	78 participants	196 participants
		1 0.5%	0 0.0%	3 1.5%
Sodium: >=160 mmol/L	Number Analyzed	196 participants	78 participants	196 participants
		0 0.0%	0 0.0%	0 0.0%
Potassium: <3 mmol/L	Number Analyzed	196 participants	78 participants	196 participants
		0 0.0%	1 1.3%	0 0.0%
Potassium: >=5.5 mmol/L	Number Analyzed	196 participants	78 participants	196 participants
		5 2.6%	5 6.4%	11 5.6%
Chloride: <80 mmol/L	Number Analyzed	196 participants	78 participants	196 participants
		0 0.0%	1 1.3%	0 0.0%
Chloride: >115 mmol/L	Number Analyzed	196 participants	78 participants	196 participants
		1 0.5%	0 0.0%	0 0.0%
Creatinine: >=150 mcmol/L (Adults)	Number Analyzed	196 participants	78 participants	196 participants
		50 25.5%	21 26.9%	70 35.7%
Creatinine: >=30% change from Baseline	Number Analyzed	196 participants	78 participants	196 participants
		12 6.1%	18 23.1%	25 12.8%
Creatinine: >=100% change from Baseline	Number Analyzed	196 participants	78 participants	196 participants
		0 0.0%	1 1.3%	4 2.0%
Urea Nitrogen: >=17 mmol/L	Number Analyzed	196 participants	78 participants	196 participants
		1 0.5%	0 0.0%	6 3.1%
ALT: > 3 ULN	Number Analyzed	196 participants	78 participants	196 participants
		0 0.0%	0 0.0%	0 0.0%
AST: >3 ULN	Number Analyzed	196 participants	78 participants	196 participants
		0 0.0%	0 0.0%	0 0.0%
Alkaline Phosphatase: >1.5 ULN	Number Analyzed	196 participants	78 participants	196 participants
		3 1.5%	0 0.0%	0 0.0%
Total Bilirubin: >1.5 ULN	Number Analyzed	196 participants	78 participants	196 participants
		2 1.0%	0 0.0%	1 0.5%
Total Bilirubin: >2 ULN	Number Analyzed	196 participants	78 participants	196 participants
		0 0.0%	0 0.0%	0 0.0%
ALT >3 ULN and Bilirubin >2 ULN	Number Analyzed	196 participants	78 participants	196 participants
		0 0.0%	0 0.0%	0 0.0%
Direct Bilirubin >35% Bilirubin and Bilirubin >1.5 ULN	Number Analyzed	195 participants	78 participants	196 participants
		2 1.0%	0 0.0%	0 0.0%

15. Secondary Outcome

Title	Number of Participants With Potentially and Clinically Significant Abnormalities: Urinalysis: Combined Stage 1 and Stage 2
Description	Criteria for potentially clinically significant abnormalities: Urine pH: <=4.6 and >=8.
Time Frame	From the first IMP administration up to the last IMP administration in EFC15392 study + 30 days (i.e., up to 25 months) or up to the first visit in LTS15823 study, whichever comes earlier

Outcome Measure Data

Analysis Population Description

Analysis was performed on extended Combined Stage 1 and Stage 2 safety population. Here, "number analyzed" signifies participants with available data for each specified category. Data for this OM was planned to be collected and analyzed for combined Stage 1 and Stage 2 population as pre-specified in protocol.

Arm/Group Title		Placebo	Venglustat 8 mg	Venglustat 15 mg
Arm/Group Description:		All participants from Stage 1 or Stage 2 were randomized to receive placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	All participants from Stage 1 or Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.
Overall Number of Participants Analyzed		200	78	199
Measure Type: Count of Participants; Unit of Measure: Participants
Urine pH: <=4.6	Number Analyzed	156 participants	70 participants	153 participants
		0 0.0%	0 0.0%	0 0.0%
Urine pH: >=8	Number Analyzed	156 participants	70 participants	153 participants
		0 0.0%	0 0.0%	0 0.0%

16. Secondary Outcome

Title	Number of Participants With Potentially and Clinically Significant Abnormalities: Vital Signs: Combined Stage 1 and Stage 2
Description	Criteria for potentially clinically significant abnormalities: Sitting Systolic Blood Pressure: <=95 millimeters of Mercury (mmHg) and decrease from Baseline >=20 mmHg; >=160 mmHg and increase from Baseline >=20 mmHg; Sitting Diastolic Blood Pressure: <=45 mmHg and decrease from Baseline >=10 mmHg, >=110 mmHg and increase from Baseline >=10 mmHg; Sitting Heart Rate: <=50 beats/minute and decrease from Baseline >=20 beats/minute; >=120 beats/minute and increase from Baseline >=20 beats/minute; and Weight: >=5% decrease from Baseline; >=5% increase from Baseline.
Time Frame	From the first IMP administration up to the last IMP administration in EFC15392 study + 30 days (i.e., up to 25 months) or up to the first visit in LTS15823 study, whichever comes earlier

Outcome Measure Data

Analysis Population Description

Analysis was performed on extended Combined Stage 1 and Stage 2 safety population. Here, "number analyzed" signifies participants with available data for each specified category. Data for this OM was planned to be collected and analyzed for combined Stage 1 and Stage 2 population as pre-specified in protocol.

Arm/Group Title		Placebo	Venglustat 8 mg	Venglustat 15 mg
Arm/Group Description:		All participants from Stage 1 or Stage 2 were randomized to receive placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	All participants from Stage 1 or Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.
Overall Number of Participants Analyzed		200	78	199
Measure Type: Count of Participants; Unit of Measure: Participants
Sitting Systolic Blood Pressure: <=95 mmHg and decrease from Baseline >=20 mmHg	Number Analyzed	196 participants	78 participants	196 participants
		0 0.0%	0 0.0%	1 0.5%
Sitting Systolic Blood Pressure: >=160 mmHg and increase from Baseline >=20 mmHg	Number Analyzed	196 participants	78 participants	196 participants
		2 1.0%	3 3.8%	10 5.1%
Sitting Diastolic Blood Pressure: <= 45 mmHg and decrease from Baseline >=10 mmHg	Number Analyzed	196 participants	78 participants	196 participants
		0 0.0%	0 0.0%	0 0.0%
Sitting Diastolic Blood Pressure: >=110 mmHg and increase from Baseline >=10 mmHg	Number Analyzed	196 participants	78 participants	196 participants
		2 1.0%	4 5.1%	7 3.6%
Sitting Heart Rate: <=50 beats/min and decrease from Baseline >=20 beats/min	Number Analyzed	196 participants	78 participants	196 participants
		0 0.0%	2 2.6%	2 1.0%
Sitting Heart Rate: >=120 beats/min and increase from Baseline >=20 beats/min	Number Analyzed	196 participants	78 participants	196 participants
		0 0.0%	0 0.0%	0 0.0%
Weight: >=5% decrease from Baseline	Number Analyzed	156 participants	70 participants	155 participants
		11 7.1%	4 5.7%	13 8.4%
Weight: >=5% increase from Baseline	Number Analyzed	156 participants	70 participants	155 participants
		15 9.6%	9 12.9%	15 9.7%

17. Secondary Outcome

Title	Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram: Combined Stage 1 and Stage 2
Description	Criteria for potentially clinically significant abnormalities: Heart Rate: <50 beats/minute; <50 beats/minute and decrease from Baseline >=20 beats/minute; <40 beats/minute; <40 beats/minute and decrease from Baseline >=20 beats/min; <30 beats/minute; >90 beats/minute; >90 beats/minute and increase from Baseline >=20 beats/minute; >100 beats/minute; >100 beats/minute and increase from Baseline >=20 beats/minute; >120 beats/minute; >120 beats/minute, increase from Baseline >=20 beats/minute; PR Interval: >200 milliseconds (msec); >200 msec and increase from Baseline >=25%; >220 msec, >240 msec; QRS Interval: >110 msec; >110 msec and increase from Baseline >=25%; >120 msec; >120 msec and increase from Baseline >=25%; QT Interval: >500 msec; QT corrected for heart rate (QTc) Bazett: >450 msec; >480 msec; increase from Baseline (30-60) msec; increase from Baseline >60 msec; QTc Fridericia: >450 msec; >480 msec; increase from Baseline (30-60) msec and increase from Baseline > 60 msec.
Time Frame	From the first IMP administration up to the last IMP administration in EFC15392 study + 30 days (i.e., up to 25 months) or up to the first visit in LTS15823 study, whichever comes earlier

Outcome Measure Data

Analysis Population Description

Analysis was performed on extended Combined Stage 1 and Stage 2 safety population. Here, "number analyzed" signifies participants with available data for each specified category. Data for this OM was planned to be collected and analyzed for combined Stage 1 and Stage 2 population as pre-specified in protocol.

Arm/Group Title		Placebo	Venglustat 8 mg	Venglustat 15 mg
Arm/Group Description:		All participants from Stage 1 or Stage 2 were randomized to receive placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	All participants from Stage 1 or Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.
Overall Number of Participants Analyzed		200	78	199
Measure Type: Count of Participants; Unit of Measure: Participants
Heart Rate: <50 beats/min	Number Analyzed	140 participants	70 participants	132 participants
		7 5.0%	6 8.6%	13 9.8%
Heart Rate: <50 beats/min and decrease from Baseline >=20 beats/min	Number Analyzed	140 participants	70 participants	132 participants
		1 0.7%	0 0.0%	1 0.8%
Heart Rate: <40 beats/min	Number Analyzed	140 participants	70 participants	132 participants
		0 0.0%	1 1.4%	1 0.8%
Heart Rate: <40 beats/min and decrease from Baseline >=20 beats/min	Number Analyzed	140 participants	70 participants	132 participants
		0 0.0%	0 0.0%	0 0.0%
Heart Rate: <30 beats/min	Number Analyzed	140 participants	70 participants	132 participants
		0 0.0%	0 0.0%	0 0.0%
Heart Rate: >90 beats/min	Number Analyzed	140 participants	70 participants	132 participants
		4 2.9%	2 2.9%	3 2.3%
Heart Rate: >90 beats/min and increase from Baseline >=20 beats/min	Number Analyzed	140 participants	70 participants	132 participants
		2 1.4%	2 2.9%	2 1.5%
Heart Rate: >100 beats/min	Number Analyzed	140 participants	70 participants	132 participants
		1 0.7%	0 0.0%	2 1.5%
Heart Rate: >100 beats/min and increase from Baseline >=20 beats/min	Number Analyzed	140 participants	70 participants	132 participants
		1 0.7%	0 0.0%	1 0.8%
Heart Rate: >120 beats/min	Number Analyzed	140 participants	78 participants	132 participants
		0 0.0%	0 0.0%	0 0.0%
Heart Rate: >120 beats/min and increase from Baseline >=20 beats/min	Number Analyzed	140 participants	70 participants	132 participants
		0 0.0%	0 0.0%	0 0.0%
PR Interval: >200 msec	Number Analyzed	140 participants	70 participants	132 participants
		8 5.7%	2 2.9%	10 7.6%
PR Interval: >200 msec and increase from Baseline >=25%	Number Analyzed	140 participants	70 participants	132 participants
		0 0.0%	0 0.0%	0 0.0%
PR Interval: >220 msec	Number Analyzed	140 participants	70 participants	132 participants
		1 0.7%	0 0.0%	2 1.5%
PR Interval: >240 msec	Number Analyzed	140 participants	70 participants	132 participants
		0 0.0%	0 0.0%	0 0.0%
QRS Interval: >110 msec	Number Analyzed	140 participants	70 participants	132 participants
		11 7.9%	4 5.7%	10 7.6%
QRS Interval: > 110 msec and increase from Baseline >=25%	Number Analyzed	140 participants	70 participants	132 participants
		0 0.0%	0 0.0%	1 0.8%
QRS Interval: >120 msec	Number Analyzed	140 participants	70 participants	132 participants
		2 1.4%	1 1.4%	3 2.3%
QRS Interval: >120 msec and increase from Baseline >=25%	Number Analyzed	140 participants	70 participants	132 participants
		0 0.0%	0 0.0%	1 0.8%
QT Interval: >500 msec	Number Analyzed	140 participants	70 participants	132 participants
		0 0.0%	0 0.0%	0 0.0%
QTc Bazett: >450 msec	Number Analyzed	140 participants	70 participants	132 participants
		5 3.6%	2 2.9%	3 2.3%
QTc Bazett: >480 msec	Number Analyzed	140 participants	70 participants	132 participants
		0 0.0%	0 0.0%	0 0.0%
QTc Bazett: Increase from Baseline [30-60] msec	Number Analyzed	136 participants	68 participants	128 participants
		13 9.6%	1 1.5%	5 3.9%
QTc Bazett: Increase from Baseline >60 msec	Number Analyzed	136 participants	68 participants	128 participants
		0 0.0%	0 0.0%	0 0.0%
QTc Fridericia: >450 msec	Number Analyzed	140 participants	70 participants	132 participants
		4 2.9%	1 1.4%	2 1.5%
QTc Fridericia: >480 msec	Number Analyzed	140 participants	70 participants	132 participants
		0 0.0%	0 0.0%	0 0.0%
QTc Fridericia: Increase from Baseline [30-60] msec	Number Analyzed	136 participants	68 participants	128 participants
		5 3.7%	1 1.5%	3 2.3%
QTc Fridericia: Increase from Baseline >60 msec	Number Analyzed	136 participants	68 participants	128 participants
		0 0.0%	0 0.0%	0 0.0%

18. Secondary Outcome

Title	Number of Participants With Physical Examination Abnormalities: Combined Stage 1 and Stage 2
Description	Physical examination included: Head, Heart, Lung, Abdomen, Musculo/Skeletal, Skin, and Mental Status. Abnormality in physical examination was based on investigator's discretion. Results are based on the treatment emergent period which was defined as time from the first IMP administration up to the last IMP administration in EFC15392 study + 30 days or up to the first visit in LTS15823 study, whichever comes earlier.
Time Frame	Baseline, Month 18, Month 24

Outcome Measure Data

Analysis Population Description

Analysis was performed on extended Combined Stage 1 and Stage 2 safety population. Here, "number analyzed" signifies participants with available data for each specified category. Data for this OM was planned to be collected and analyzed for combined Stage 1 and Stage 2 population as pre-specified in protocol.

Arm/Group Title		Placebo	Venglustat 8 mg	Venglustat 15 mg
Arm/Group Description:		All participants from Stage 1 or Stage 2 were randomized to receive placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	All participants from Stage 1 or Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.
Overall Number of Participants Analyzed		200	78	199
Measure Type: Count of Participants; Unit of Measure: Participants
Baseline: Head	Number Analyzed	200 participants	78 participants	198 participants
		1 0.5%	1 1.3%	4 2.0%
Baseline: Heart	Number Analyzed	200 participants	78 participants	198 participants
		2 1.0%	1 1.3%	1 0.5%
Baseline: Lung	Number Analyzed	200 participants	78 participants	198 participants
		0 0.0%	0 0.0%	0 0.0%
Baseline: Abdomen	Number Analyzed	200 participants	78 participants	198 participants
		15 7.5%	12 15.4%	24 12.1%
Baseline: Musculo/Skeletal	Number Analyzed	199 participants	78 participants	198 participants
		5 2.5%	1 1.3%	4 2.0%
Baseline: Skin	Number Analyzed	199 participants	78 participants	198 participants
		7 3.5%	2 2.6%	3 1.5%
Baseline: Mental Status	Number Analyzed	200 participants	78 participants	198 participants
		0 0.0%	0 0.0%	0 0.0%
Month 18: Head	Number Analyzed	49 participants	49 participants	47 participants
		0 0.0%	0 0.0%	1 2.1%
Month 18: Heart	Number Analyzed	49 participants	49 participants	47 participants
		0 0.0%	0 0.0%	1 2.1%
Month 18: Lung	Number Analyzed	49 participants	49 participants	47 participants
		0 0.0%	0 0.0%	0 0.0%
Month 18: Abdomen	Number Analyzed	49 participants	49 participants	47 participants
		2 4.1%	1 2.0%	0 0.0%
Month 18: Musculo/Skeletal	Number Analyzed	49 participants	49 participants	47 participants
		0 0.0%	0 0.0%	1 2.1%
Month 18: Skin	Number Analyzed	49 participants	49 participants	47 participants
		1 2.0%	1 2.0%	0 0.0%
Month 18: Mental Status	Number Analyzed	49 participants	49 participants	47 participants
		1 2.0%	0 0.0%	0 0.0%
Month 24: Head	Number Analyzed	7 participants	4 participants	7 participants
		0 0.0%	0 0.0%	0 0.0%
Month 24: Heart	Number Analyzed	7 participants	4 participants	7 participants
		0 0.0%	0 0.0%	0 0.0%
Month 24: Lung	Number Analyzed	7 participants	4 participants	7 participants
		0 0.0%	0 0.0%	0 0.0%
Month 24: Abdomen	Number Analyzed	7 participants	4 participants	7 participants
		0 0.0%	0 0.0%	0 0.0%
Month 24: Musculo/Skeletal	Number Analyzed	7 participants	4 participants	7 participants
		0 0.0%	0 0.0%	0 0.0%
Month 24: Skin	Number Analyzed	7 participants	4 participants	7 participants
		0 0.0%	0 0.0%	0 0.0%
Month 24: Mental Status	Number Analyzed	7 participants	4 participants	7 participants
		0 0.0%	0 0.0%	0 0.0%

19. Secondary Outcome

Title	Change From Baseline in Beck Depression Inventory-II (BDI-II) Score: Combined Stage 1 and Stage 2
Description	The Beck Depression Inventory-II (BDI-II) is a 21-item questionnaire used to assess depression. Most items are rated on a 4-point scale from 0 to 3, and a few items are rated on a 7-point scale. Individual item scores are added to get a total BDI-II score from 0 to 63. The higher the total score, the more severe the depression, and the lower the total score, the less severe the depression.
Time Frame	Baseline, Months 3, 6, 9, 12, 15, 18, 21, and 24, Last on-treatment value up to last IMP + 1 day (anytime during the maximum duration of 25 months)

Outcome Measure Data

Analysis Population Description

Analysis was performed on extended Combined Stage 1 and Stage 2 safety population. Here, "number analyzed" signifies participants with available data for each specified category. Data for this OM was planned to be collected and analyzed for combined Stage 1 and Stage 2 population as pre-specified in protocol.

Arm/Group Title		Placebo	Venglustat 8 mg	Venglustat 15 mg
Arm/Group Description:		All participants from Stage 1 or Stage 2 were randomized to receive placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	All participants from Stage 1 or Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.
Overall Number of Participants Analyzed		200	78	199
Mean (Standard Deviation); Unit of Measure: score on a scale
Baseline	Number Analyzed	191 participants	77 participants	194 participants
		4.0 (4.7)	3.0 (4.1)	3.4 (4.1)
Change at Month 3	Number Analyzed	147 participants	73 participants	153 participants
		-0.1 (4.0)	0.7 (4.0)	0.7 (4.3)
Change at Month 6	Number Analyzed	122 participants	68 participants	128 participants
		-0.6 (4.2)	0.9 (4.2)	0.3 (3.9)
Change at Month 9	Number Analyzed	92 participants	67 participants	100 participants
		-0.3 (4.8)	0.1 (3.7)	0.7 (4.9)
Change at Month 12	Number Analyzed	58 participants	61 participants	63 participants
		-1.9 (3.9)	0.2 (4.7)	1.5 (5.3)
Change at Month 15	Number Analyzed	54 participants	56 participants	54 participants
		-1.5 (4.4)	-0.1 (4.4)	-0.3 (4.0)
Change at Month 18	Number Analyzed	42 participants	46 participants	43 participants
		-1.0 (4.9)	0.5 (3.0)	0.0 (3.5)
Change at Month 21	Number Analyzed	24 participants	28 participants	32 participants
		1.0 (9.5)	-0.1 (1.3)	1.1 (2.8)
Change at Month 24	Number Analyzed	4 participants	4 participants	7 participants
		-0.3 (0.5)	0.8 (2.2)	0.3 (1.7)
Change at Last on-treatment value	Number Analyzed	155 participants	74 participants	164 participants
		-0.5 (5.1)	0.1 (4.0)	0.3 (4.6)

20. Secondary Outcome

Title	Number of Participants With Worsening Lens Opacity From Baseline During the Treatment-emergent Period: Combined Stage 1 and Stage 2
Description	Worsening of lens opacity classification system (LOCS) III score or World Health Organization (WHO) grade in nuclear opacification, cortical opacification and posterior subcapsular opacification were assessed for 'Any eye', 'Unilateral' and 'Bilateral' separately. A participant could be counted in all the 3 categories. In each category, the worst case was taken into account. To be evaluable for 'Any', a participant had to have at least one eye evaluable, whereas, for 'Unilateral' and 'Bilateral', a participant had to have both eyes evaluable. Therefore, the sum of 'Unilateral' + 'Bilateral' is not necessarily equal to 'Any' in the below table. The difference observed in 'Nuclear Opacification' in 15 mg group, comes from that 1 participant who had Unilateral worsening at a given visit and a Bilateral worsening at another visit. Therefore, this participant was counted as 'Unilateral', 'Bilateral' and counted only once in 'Any'. Results are based on the TE period.
Time Frame	From the first IMP administration up to the last IMP administration in EFC15392 study + 30 days (i.e., up to 25 months) or up to the first visit in LTS15823 study, whichever comes earlier

Outcome Measure Data

Analysis Population Description

Analysis was performed on extended Combined Stage 1 and Stage 2 safety population. Here, "number analyzed" signifies participants with available data for each specified category. Data for this OM was planned to be collected and analyzed for combined Stage 1 and Stage 2 population as pre-specified in protocol. TE period: time from first IMP administration up to the last IMP administration in EFC15392 study + 30 days or up to the first visit in LTS15823 study, whichever comes earlier.

Arm/Group Title		Placebo	Venglustat 8 mg	Venglustat 15 mg
Arm/Group Description:		All participants from Stage 1 or Stage 2 were randomized to receive placebo matched to venglustat once daily for treatment period of 24 months.	Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.	All participants from Stage 1 or Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.
Overall Number of Participants Analyzed		200	78	199
Measure Type: Count of Participants; Unit of Measure: Participants
Worsening of LOCS III score >= 0.5 or WHO grade >= 1.0 in nuclear opacification: Any eye	Number Analyzed	91 participants	61 participants	98 participants
		8 8.8%	3 4.9%	9 9.2%
Worsening of LOCS III score >= 0.5 or WHO grade >= 1.0 in nuclear opacification: Unilateral	Number Analyzed	91 participants	61 participants	98 participants
		0 0.0%	0 0.0%	4 4.1%
Worsening of LOCS III score >= 0.5 or WHO grade >= 1.0 in nuclear opacification: Bilateral	Number Analyzed	91 participants	61 participants	98 participants
		8 8.8%	3 4.9%	6 6.1%
Worsening of LOCS III score >= 0.8 or WHO grade >= 1.0 in cortical opacification: Any eye	Number Analyzed	84 participants	61 participants	87 participants
		4 4.8%	4 6.6%	4 4.6%
Worsening of LOCS III score >= 0.8 or WHO grade >= 1.0 in cortical opacification: Unilateral	Number Analyzed	83 participants	61 participants	87 participants
		1 1.2%	0 0.0%	1 1.1%
Worsening of LOCS III score >= 0.8 or WHO grade >= 1.0 in cortical opacification: Bilateral	Number Analyzed	83 participants	61 participants	87 participants
		2 2.4%	4 6.6%	3 3.4%
Worsening of LOCS III score>=0.5 or WHO grade >= 1.0 in posterior subcapsular opacification:Any eye	Number Analyzed	81 participants	56 participants	87 participants
		2 2.5%	2 3.6%	3 3.4%
Worsening of LOCS III score>=0.5 or WHO grade >=1.0 in posterior subcapsularopacification:Unilateral	Number Analyzed	81 participants	56 participants	87 participants
		0 0.0%	1 1.8%	1 1.1%
Worsening of LOCS III score>=0.5 or WHO grade >=1.0 in posterior subcapsular opacification:Bilateral	Number Analyzed	81 participants	56 participants	87 participants
		2 2.5%	1 1.8%	2 2.3%

Adverse Events

Time Frame	From the first IMP administration up to the last IMP administration in EFC15392 study + 30 days (i.e., up to 25 months) or up to the first visit in LTS15823 study, whichever comes earlier
Adverse Event Reporting Description	Reported AEs were TEAEs that developed/worsened in grade or became serious during TE period (time from the first IMP administration up to the last IMP administration in EFC15392 study + 30 days or up to the first visit in LTS15823 study, whichever comes earlier). Analysis was performed on the Stage 1 and Stage 2 safety population.
Arm/Group Title	Stage 1- Placebo		Stage 1- Venglustat 8 mg		Stage 1- Venglustat 15 mg		Stage 2- Placebo		Stage 2- Venglustat 15 mg
Arm/Group Description	Participants from Stage 1 were randomized to receive 2 capsules of placebo matched to venglustat once daily for treatment period of 24 months.		Participants from Stage 1 were randomized to receive venglustat 8 mg (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.		Participants from Stage 1 were randomized to receive 1 capsule of venglustat 15 mg and 1 capsule of placebo matched to venglustat once daily for treatment period of 24 months.		Participants from Stage 2 were randomized to receive 1 capsule of placebo matched to venglustat once daily for treatment period of 24 months.		Participants from Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.
All-Cause Mortality
	Stage 1- Placebo		Stage 1- Venglustat 8 mg		Stage 1- Venglustat 15 mg		Stage 2- Placebo		Stage 2- Venglustat 15 mg
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/78 (0.00%)		0/78 (0.00%)		0/80 (0.00%)		0/122 (0.00%)		0/119 (0.00%)
Serious Adverse Events
	Stage 1- Placebo		Stage 1- Venglustat 8 mg		Stage 1- Venglustat 15 mg		Stage 2- Placebo		Stage 2- Venglustat 15 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/78 (10.26%)		15/78 (19.23%)		19/80 (23.75%)		6/122 (4.92%)		7/119 (5.88%)
Cardiac disorders
Arteriosclerosis Coronary Artery † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	0/80 (0.00%)	0	1/122 (0.82%)	1	0/119 (0.00%)	0
Coronary Artery Stenosis † 1	0/78 (0.00%)	0	1/78 (1.28%)	2	0/80 (0.00%)	0	0/122 (0.00%)	0	0/119 (0.00%)	0
Mitral Valve Incompetence † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	0/80 (0.00%)	0	1/122 (0.82%)	2	0/119 (0.00%)	0
Supraventricular Tachycardia † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	0/80 (0.00%)	0	1/122 (0.82%)	1	0/119 (0.00%)	0
Gastrointestinal disorders
Dental Cyst † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	1	0/122 (0.00%)	0	0/119 (0.00%)	0
Inguinal Hernia † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	0/80 (0.00%)	0	1/122 (0.82%)	1	0/119 (0.00%)	0
Large Intestinal Stenosis † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	1	0/122 (0.00%)	0	0/119 (0.00%)	0
Pancreatitis Acute † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	0/80 (0.00%)	0	0/122 (0.00%)	0	1/119 (0.84%)	1
Rectal Haemorrhage † 1	0/78 (0.00%)	0	1/78 (1.28%)	1	0/80 (0.00%)	0	0/122 (0.00%)	0	0/119 (0.00%)	0
General disorders
Haemorrhagic Cyst † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	1	0/122 (0.00%)	0	0/119 (0.00%)	0
Non-Cardiac Chest Pain † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	1	0/122 (0.00%)	0	0/119 (0.00%)	0
Hepatobiliary disorders
Hepatic Pain † 1	1/78 (1.28%)	1	0/78 (0.00%)	0	0/80 (0.00%)	0	0/122 (0.00%)	0	0/119 (0.00%)	0
Infections and infestations
Appendicitis † 1	1/78 (1.28%)	1	1/78 (1.28%)	1	2/80 (2.50%)	2	0/122 (0.00%)	0	0/119 (0.00%)	0
Covid-19 † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	0/80 (0.00%)	0	2/122 (1.64%)	2	0/119 (0.00%)	0
Diverticulitis † 1	0/78 (0.00%)	0	1/78 (1.28%)	1	1/80 (1.25%)	1	0/122 (0.00%)	0	0/119 (0.00%)	0
Gastroenteritis Viral † 1	0/78 (0.00%)	0	1/78 (1.28%)	1	0/80 (0.00%)	0	0/122 (0.00%)	0	0/119 (0.00%)	0
Infected Cyst † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	1	0/122 (0.00%)	0	0/119 (0.00%)	0
Influenza † 1	0/78 (0.00%)	0	1/78 (1.28%)	1	0/80 (0.00%)	0	0/122 (0.00%)	0	0/119 (0.00%)	0
Kidney Infection † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	2	0/122 (0.00%)	0	0/119 (0.00%)	0
Pneumonia † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	1	0/122 (0.00%)	0	0/119 (0.00%)	0
Renal Cyst Infection † 1	0/78 (0.00%)	0	3/78 (3.85%)	3	1/80 (1.25%)	1	0/122 (0.00%)	0	1/119 (0.84%)	1
Urinary Tract Infection † 1	1/78 (1.28%)	1	0/78 (0.00%)	0	2/80 (2.50%)	2	0/122 (0.00%)	0	0/119 (0.00%)	0
Injury, poisoning and procedural complications
Back Injury † 1	0/78 (0.00%)	0	1/78 (1.28%)	1	0/80 (0.00%)	0	0/122 (0.00%)	0	0/119 (0.00%)	0
Hand Fracture † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	1	0/122 (0.00%)	0	0/119 (0.00%)	0
Jaw Fracture † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	1	0/122 (0.00%)	0	0/119 (0.00%)	0
Subdural Haematoma † 1	1/78 (1.28%)	1	0/78 (0.00%)	0	0/80 (0.00%)	0	0/122 (0.00%)	0	0/119 (0.00%)	0
Tibia Fracture † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	0/80 (0.00%)	0	1/122 (0.82%)	1	0/119 (0.00%)	0
Metabolism and nutrition disorders
Fluid Overload † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	1	0/122 (0.00%)	0	0/119 (0.00%)	0
Hyperkalaemia † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	1	0/122 (0.00%)	0	0/119 (0.00%)	0
Musculoskeletal and connective tissue disorders
Flank Pain † 1	1/78 (1.28%)	1	0/78 (0.00%)	0	0/80 (0.00%)	0	0/122 (0.00%)	0	0/119 (0.00%)	0
Osteoarthritis † 1	0/78 (0.00%)	0	1/78 (1.28%)	1	0/80 (0.00%)	0	0/122 (0.00%)	0	0/119 (0.00%)	0
Rotator Cuff Syndrome † 1	1/78 (1.28%)	1	0/78 (0.00%)	0	0/80 (0.00%)	0	0/122 (0.00%)	0	0/119 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal Cell Carcinoma † 1	1/78 (1.28%)	1	0/78 (0.00%)	0	0/80 (0.00%)	0	0/122 (0.00%)	0	0/119 (0.00%)	0
Breast Cancer † 1	0/78 (0.00%)	0	1/78 (1.28%)	1	0/80 (0.00%)	0	0/122 (0.00%)	0	0/119 (0.00%)	0
Intraductal Proliferative Breast Lesion † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	0/80 (0.00%)	0	0/122 (0.00%)	0	1/119 (0.84%)	1
Invasive Ductal Breast Carcinoma † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	0/80 (0.00%)	0	0/122 (0.00%)	0	1/119 (0.84%)	1
Mediastinum Neoplasm † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	0/80 (0.00%)	0	0/122 (0.00%)	0	1/119 (0.84%)	1
Nervous system disorders
Carpal Tunnel Syndrome † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	1	0/122 (0.00%)	0	0/119 (0.00%)	0
Intracranial Aneurysm † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	1	0/122 (0.00%)	0	0/119 (0.00%)	0
Loss Of Consciousness † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	0/80 (0.00%)	0	0/122 (0.00%)	0	1/119 (0.84%)	1
Polyneuropathy † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	1	0/122 (0.00%)	0	0/119 (0.00%)	0
Syncope † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	1	0/122 (0.00%)	0	0/119 (0.00%)	0
Psychiatric disorders
Depression † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	1	0/122 (0.00%)	0	0/119 (0.00%)	0
Suicidal Ideation † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	1	0/122 (0.00%)	0	0/119 (0.00%)	0
Renal and urinary disorders
Acute Kidney Injury † 1	0/78 (0.00%)	0	1/78 (1.28%)	1	0/80 (0.00%)	0	0/122 (0.00%)	0	0/119 (0.00%)	0
Calculus Urinary † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	0/80 (0.00%)	0	0/122 (0.00%)	0	1/119 (0.84%)	1
Chronic Kidney Disease † 1	1/78 (1.28%)	1	0/78 (0.00%)	0	0/80 (0.00%)	0	0/122 (0.00%)	0	0/119 (0.00%)	0
Haematuria † 1	0/78 (0.00%)	0	3/78 (3.85%)	3	0/80 (0.00%)	0	0/122 (0.00%)	0	0/119 (0.00%)	0
Renal Cyst Haemorrhage † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	0/80 (0.00%)	0	0/122 (0.00%)	0	2/119 (1.68%)	2
Renal Cyst Ruptured † 1	0/78 (0.00%)	0	2/78 (2.56%)	2	0/80 (0.00%)	0	0/122 (0.00%)	0	0/119 (0.00%)	0
Renal Haemorrhage † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	2	0/122 (0.00%)	0	0/119 (0.00%)	0
Ureterolithiasis † 1	0/78 (0.00%)	0	1/78 (1.28%)	1	0/80 (0.00%)	0	0/122 (0.00%)	0	0/119 (0.00%)	0
Reproductive system and breast disorders
Adenomyosis † 1	0/78 (0.00%)	0	0/78 (0.00%)	0	1/80 (1.25%)	1	0/122 (0.00%)	0	0/119 (0.00%)	0
Skin and subcutaneous tissue disorders
Rash † 1	1/78 (1.28%)	1	0/78 (0.00%)	0	0/80 (0.00%)	0	0/122 (0.00%)	0	0/119 (0.00%)	0
1 Term from vocabulary, MedDRA 24.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Stage 1- Placebo		Stage 1- Venglustat 8 mg		Stage 1- Venglustat 15 mg		Stage 2- Placebo		Stage 2- Venglustat 15 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/78 (53.85%)		46/78 (58.97%)		48/80 (60.00%)		32/122 (26.23%)		48/119 (40.34%)
Eye disorders
Cataract Cortical † 1	5/78 (6.41%)	5	2/78 (2.56%)	4	3/80 (3.75%)	3	1/122 (0.82%)	1	2/119 (1.68%)	2
Cataract Nuclear † 1	5/78 (6.41%)	5	2/78 (2.56%)	2	3/80 (3.75%)	4	1/122 (0.82%)	1	2/119 (1.68%)	2
Dry Eye † 1	5/78 (6.41%)	5	0/78 (0.00%)	0	2/80 (2.50%)	2	1/122 (0.82%)	1	0/119 (0.00%)	0
Gastrointestinal disorders
Constipation † 1	0/78 (0.00%)	0	4/78 (5.13%)	4	3/80 (3.75%)	3	0/122 (0.00%)	0	8/119 (6.72%)	8
Diarrhoea † 1	2/78 (2.56%)	4	0/78 (0.00%)	0	6/80 (7.50%)	6	3/122 (2.46%)	3	2/119 (1.68%)	2
Dyspepsia † 1	4/78 (5.13%)	5	1/78 (1.28%)	1	0/80 (0.00%)	0	1/122 (0.82%)	1	2/119 (1.68%)	2
Nausea † 1	1/78 (1.28%)	1	6/78 (7.69%)	6	7/80 (8.75%)	9	0/122 (0.00%)	0	6/119 (5.04%)	6
General disorders
Fatigue † 1	1/78 (1.28%)	1	4/78 (5.13%)	5	9/80 (11.25%)	9	3/122 (2.46%)	3	2/119 (1.68%)	2
Influenza Like Illness † 1	1/78 (1.28%)	1	5/78 (6.41%)	5	1/80 (1.25%)	1	1/122 (0.82%)	2	0/119 (0.00%)	0
Infections and infestations
Covid-19 † 1	5/78 (6.41%)	5	6/78 (7.69%)	6	1/80 (1.25%)	1	3/122 (2.46%)	3	7/119 (5.88%)	7
Conjunctivitis † 1	4/78 (5.13%)	5	0/78 (0.00%)	0	1/80 (1.25%)	1	1/122 (0.82%)	1	1/119 (0.84%)	1
Influenza † 1	4/78 (5.13%)	4	3/78 (3.85%)	3	0/80 (0.00%)	0	1/122 (0.82%)	1	0/119 (0.00%)	0
Nasopharyngitis † 1	10/78 (12.82%)	13	5/78 (6.41%)	5	6/80 (7.50%)	9	2/122 (1.64%)	2	0/119 (0.00%)	0
Upper Respiratory Tract Infection † 1	0/78 (0.00%)	0	4/78 (5.13%)	4	6/80 (7.50%)	8	4/122 (3.28%)	4	6/119 (5.04%)	7
Urinary Tract Infection † 1	6/78 (7.69%)	6	5/78 (6.41%)	6	7/80 (8.75%)	15	3/122 (2.46%)	4	1/119 (0.84%)	1
Musculoskeletal and connective tissue disorders
Arthralgia † 1	4/78 (5.13%)	4	3/78 (3.85%)	3	2/80 (2.50%)	2	2/122 (1.64%)	2	2/119 (1.68%)	2
Back Pain † 1	8/78 (10.26%)	9	6/78 (7.69%)	7	8/80 (10.00%)	8	5/122 (4.10%)	5	2/119 (1.68%)	2
Flank Pain † 1	3/78 (3.85%)	3	1/78 (1.28%)	1	5/80 (6.25%)	5	1/122 (0.82%)	1	0/119 (0.00%)	0
Pain In Extremity † 1	0/78 (0.00%)	0	4/78 (5.13%)	4	0/80 (0.00%)	0	1/122 (0.82%)	1	0/119 (0.00%)	0
Nervous system disorders
Dizziness † 1	2/78 (2.56%)	2	4/78 (5.13%)	4	4/80 (5.00%)	4	2/122 (1.64%)	2	3/119 (2.52%)	3
Headache † 1	6/78 (7.69%)	6	8/78 (10.26%)	9	11/80 (13.75%)	14	7/122 (5.74%)	8	8/119 (6.72%)	8
Renal and urinary disorders
Haematuria † 1	3/78 (3.85%)	3	4/78 (5.13%)	5	0/80 (0.00%)	0	4/122 (3.28%)	5	2/119 (1.68%)	2
Respiratory, thoracic and mediastinal disorders
Cough † 1	1/78 (1.28%)	1	5/78 (6.41%)	8	8/80 (10.00%)	8	1/122 (0.82%)	1	7/119 (5.88%)	8
Vascular disorders
Hypertension † 1	2/78 (2.56%)	2	5/78 (6.41%)	5	7/80 (8.75%)	7	4/122 (3.28%)	4	4/119 (3.36%)	4
1 Term from vocabulary, MedDRA 24.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

Following decision to discontinue EFC15392 based on the futility analysis, the two-steps analysis initially planned were not applicable, therefore only the final analysis of all safety endpoints (laboratory, vital sign, ECG, physical examination, BDI-II, and lens opacity) were performed on extended combined Stage 1 and Stage 2 safety population only.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.

Results Point of Contact

• Name/Title: Trial Transparency Team
• Organization: Sanofi aventis recherche & développement
• Phone: 800-633-1610 ext 6#
• EMail: Contact-US@sanofi.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Perrone RD, Hariri A, Minini P, Ahn C, Chapman AB, Horie S, Knebelmann B, Mrug M, Ong ACM, Pei YPC, Torres VE, Modur V, Gansevoort RT. The STAGED-PKD 2-Stage Adaptive Study With a Patient Enrichment Strategy and Treatment Effect Modeling for Improved Study Design Efficiency in Patients With ADPKD. Kidney Med. 2022 Aug 27;4(10):100538. doi: 10.1016/j.xkme.2022.100538. eCollection 2022 Oct.

• Responsible Party: Sanofi ( Genzyme, a Sanofi Company )
• ClinicalTrials.gov Identifier: NCT03523728
• Other Study ID Numbers: EFC15392; 2017-004084-12 ( EudraCT Number ); U1111-1202-0775 ( Other Identifier: UTN )
• First Submitted: May 1, 2018
• First Posted: May 14, 2018
• Results First Submitted: July 29, 2022
• Results First Posted: November 9, 2022
• Last Update Posted: November 9, 2022